RESUMO
SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.
Assuntos
Transtornos da Pigmentação/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Deleção de Sequência , Paraplegia Espástica Hereditária/genética , Vitiligo/genética , Sequência de Aminoácidos , Animais , Apoptose/genética , Povo Asiático/genética , Cromossomos Humanos Par 1/genética , Éxons , Fácies , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Ligação Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Células NIH 3T3 , Linhagem , Transtornos da Pigmentação/diagnóstico , Paraplegia Espástica Hereditária/diagnóstico , Vitiligo/diagnóstico , Adulto JovemRESUMO
BACKGROUND: The clinical manifestations of lipodermatosclerosis (LDS) may mimic cellulitis and various panniculitides. METHODS: To better characterize the histopathologic changes of LDS, we reviewed the clinicopathologic findings of 26 cases with a pathologic diagnosis consistent with LDS. A final diagnosis of LDS was made in 17 cases based on the clinicopathological correlation. As some cases manifested erythema nodosum (EN)-like lesions, 14 specimens of EN were reviewed to identify features for differential diagnosis. RESULTS: Microscopically, the acute LDS lesions were characterized by patchy hemorrhage, ischemic fat necrosis with lipophages or hyalinization in the fat lobules. As the disease progressed to the subacute and chronic stages, lipomembranous or membranocystic fat necrosis, septal fibrosis and background venous stasis in the dermis became more pronounced. In contrast, EN typically displayed minimal venous stasis and membranocystic fat necrosis. CONCLUSIONS: LDS may manifest as EN-like lesions. Therefore LDS should be included in the differential diagnosis of EN. Clinicopathologic correlation is essential for diagnosis. Differentiating the acute LDS from the early EN is more difficult. A constellation of the findings of septal/lobular panniculitis, hemorrhage in the subcutaneous tissue, and lipophages and/or ischemic fat necrosis in the fat lobules favors the diagnosis of acute LDS.